Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Abstract

The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

Determination of the role of noradrenergic and 5‐hydroxytryptaminergic neurones in postsynaptic α2‐adrenoceptor desensitization by desipramine and ECS

“…This finding of a differential necessity for an intact noradrenergic input in the attenuation of postsynaptic a2-adrenoceptors by desipramine and ECS mirrors the previously reported requirements for the down-regulation of fl-adrenoceptors by these two antidepressant treatments, i.e. noradrenergic neurones are essential for the downregulation by desipramine, but not ECS (Vetulani & Sulser, 1975;Vetulani et al, 1976a;Kellar et al, 1981;Dooley et al, 1983;Hall et al, 1984). An alternative explanation is that it is the noradrenergic neurone (or possibly a cotransmitter contained within it), rather than noradrenaline per se which is essential for the down-regulation of a2-adrenoceptors by desipramine.…”

“…However, the concept that down-regulation results exclusively from an increase in the synaptic concentrations of these neurotransmitters is too simplistic to explain the actions of all antidepressant treatments. For example, the down-regulation of fi-adrenoceptors by desipramine is dependent upon intact noradrenergic function (Vetulani et al, 1976a;Dooley et al, 1983;Hall et al, 1984), whereas electroconvulsive shock (ECS) decreases these receptors even after destruction of noradrenergic neurones (Vetulani & Sulser, 1975;Kellar et al, 1981;Dooley et al, 1987). In addition, there is also evidence to show that antidepressant-induced adrenoceptor desensitization involves a functional interplay between central noradrenergic and 5-hydroxytryptaminergic neurones.…”

Effects of chronic oral administration of the antidepressants, desmethylimipramine and zimelidine on rat cortical GABAB binding sites: a comparison with 5‐HT2 binding site changes

“…The observed decreases in rat body weight gain after chronic administration of DMI and zimelidine have been described in other studies (Hall et al, 1984;Ask et al, 1986). A single oral dose of tricyclic antidepressants including DMI in the rat has been found to inhibit markedly food intake (Blavet & DeFeudis, 1982).…”

Serotonergic and adrenergic receptors in alcohol-preferring and non-preferring rats

“…Although the 5HT-2 receptor was found to be down-regulated in rat brain following chronic treatment with tricyclic antidepressant drugs due to their inhibition of amine uptake (Peroutka and Snyder, 1980;Blackshear and Sanders-Bush, 1982;Hyttel et al, 1984), chronic treatment with selective inhibitors of 5HT uptake (fluoxetine, zimelidine, and citalopram) did not cause a down-regulation of 5HT-2 receptor. Lesioning of 5HT neurons or inhibition of 5HT synthesis did not bring upregulation nor prevent the down-regulation of the 5HT-2 receptor by tricyclic antidepressant drugs (Hall et al, 1984). Chronic administration of a direct 5HT agonist TFPP produced a down-regulation of the 5HT-2 receptor, similar to that caused by chronic administration of mianserin, 5HT antagonist (Blackshear et al, 1986).…”